Gastric adenocarcinoma is the leading infection-associated cancer and third most common cause of global cancer mortality. Helicobacter pylori infects over half of the world's population and up to 85% of persons residing in developing nations, yet prevention programs and biomarkers are lacking to identify high risk strains and to manage patients with precancerous lesions. This Program Project Grant has made seminal contributions to gastric cancer research by utilizing extensive and well-organized infrastructures in Latin America, organized around a unique long-term cohort of human subjects from a former chemoprevention trial in the high cancer risk Andean region of Colombia. Central accomplishments include discoveries related to: 1) high risk (mountain) vs. low risk (coastal) cancer risk regions; 2) H. pylori strain phylogeographic origin and genetic mismatch between human hosts and the infecting strains that are directly linked with disease progression; 3) important disease modifiers including the gastric microbiota and concurrent parasitic infection; 4) a causal role for polyamines and specifically the oxidation of spermine by spermine oxidase (SMOX) as a cause of DNA damage, and the importance of phosphorylation of EGFR and ERBB2 as a molecular signature of gastric carcinogenesis. In this P01, in addition to the long-term follow-up of the high risk Colombian cohort, we will include new study populations in Central America, where NCI-funded infrastructures are in place, as this region represents the core low/middle income countries (LMICs) of Latin America with linkage to significant U.S. Hispanic immigrant populations. The overarching objective of this P01 renewal application is to develop new understanding of gastric carcinogenesis through studies incorporating analyses of human and H. pylori genetics, and gene methylation (Project 1), the interaction of H. pylori with parasitic infection and the gastric microbiota (Project 2), and molecular mechanisms of gastric carcinogenesis focused on novel pathways for oxidative DNA damage (Project 3). These projects each explore distinct hypothesis, but are tightly integrated in their focus on developing novel strategies for risk stratification and prevention of gastric cancer. The individua projects are: Project 1, Epidemiologic studies of gastric carcinogenesis (PI - Douglas M. Morgan); Project 2, The influence of gastric microbiota, intestinal helminths and host immune responses in cancer risk (PI - James G. Fox); Project 3, Molecular signatures of gastric carcinogenesis in the host response to H. pylori (PI - Keith T. Wilson). These studies are enriched by three cores: Histopathology (Core A); Administrative (Core B); and Fieldwork (Core C). The unique and highly developed expertise brought to this P01 includes global health and epidemiology, human and bacterial genetics, microbiology, immunology, cancer biology, pathology, and gastroenterology. Collectively, these cross-disciplinary studies are extremely well-positioned to bring to fruition bold and exciting new concepts in gastric cancer molecular epidemiology, with direct translational relevance to specific risk assessment and prevention strategies.